Spinocerebellar ataxia type 7 (SCA7) is a rare inherited neurodegenerative disorder caused by a trinucleuotide repeat mutation in the SCA7 gene that results in a polyglutamine (polyQ) tract in the ataxin-7 protein. Huntington's disease is another polyQ disease, and these are characterized by progressive movement disorders and other clinical symptoms that become more severe with each generation as the polyQ tract increases. Scientific research has shown that these polyQ-expanded proteins aggregate in neurons and cause toxicity and neurodegeneration, and this has been in polyQ-expanded ataxin-7. The objective of this project is to understand how ataxin-7 is normally broken down in neurons, and how this process is deficient in polyQ-expanded ataxin-7. In particular, we will investigate a lysosomal degradation pathway, chaperone-mediated autophagy (CMA), that targets specific proteins for degradation. There is evidence that ataxin-7 may be a target protein for CMA, but that polyQ-expanded ataxin-7 is inefficiently cleared by this mechanism. The aims of this project are to prove that ataxin-7 is a substrate for CMA and to investigate whether CMA activity is deficient in polyQ-expanded ataxin-7, and if so, the mechanism of decreased clearance. Proof-of-principle for this concept is that wild-type 1-synuclein is cleared by CMA, yet CMA activity is blocked in the mutant 1-synuclein found in some forms of familial Parkinson's disease. Our long-term objective is to manipulate native protein clearance mechanisms to enhance the clearance of polyQ-expanded ataxin-7. This has obvious consequences for understanding the cause of SCA7 - a rare yet devastating neurodegenerative disease;but also for other polyQ diseases and for all diseases that have toxic accumulation of mutant proteins. These include most neurodegenerative diseases, like Alzheimer's disease and Parkinson's disease. Furthermore, protein clearance mechanisms, including CMA, become less effective as we age. This leads to accumulation of abnormal proteins in aging cells of many tissues and organs. Therefore, investigation of native protein degradation mechanisms will provide fundamental knowledge that may be manipulated in order to enhance mutant protein clearance, with implications in neurodegeneration and aging. PUBLIC HEALTH RELEVANCE: The therapeutic aim of our research is to decrease toxic protein accumulation in the polyglutamine disease, spinocerebellar ataxia type 7 (SCA7). This fundamental knowledge potentially impacts all diseases with pathological protein accumulation, including Huntington's disease, Parkinson's disease and Alzheimer's disease - the fourth largest burden of disease in high-income countries (WHO report, 2005). The research outlined in this grant application has implications in the reduction of the burden of neurodegenerative illness as well as extending the healthy years of life.